The COVID-19 pandemic has been heavily striking the majority of countries globally since early 2020 (1). The European community of neurologists is putting an extraordinary effort to monitor the neurological symptoms and complications in patients with COVID-19 (2). However, besides the direct health burden due to the infection, restriction measures, prompted by the need for distancing, are possibly impacting many determinants of health and wellbeing (3), such as (1) social factors, (2) economic factors, (3) environmental factors, (4) individual health behaviors, and (5) access to health and social care services. The latter, in particular, was limited worldwide during the pandemic up to May 2020 for all kinds of conditions (4). Although it has been suggested that restrictions on healthcare services may be particularly burdensome for people with chronic disorders (3), the magnitude of the indirect impact of the pandemic in terms of major clinical outcomes is still not clear. Chronic neurodegenerative diseases may be a paradigmatic example of increased vulnerability during the abrupt rearrangement of healthcare services due to emergencies such as a pandemic bout (5).

Parkinson's disease (PD), atypical parkinsonism (AP), and vascular parkinsonism (VP) are neurologic chronic disorders affecting mainly older persons burdened by progressive disability, comorbidities, higher polypharmacy risk, and requiring follow-up and supportive care provided in specialized healthcare settings (6). Governmental control measures, limiting social interactions and mobility, and the restriction of healthcare services through the cancellation of outpatient appointments and scheduled hospital admissions could have caused both a reduction of individual healthy behavior (e.g., regular physical activity) as well as a limitation of timely neurologic counseling and physiotherapy.

During the first outbreak peak, from March 1 to May 31, 2020, Italy was the most hit country in Europe. The city of Bologna, the regional capital city of the Emilia-Romagna region (north-east of Italy), counted 4,636 cases in the same period. Starting from March 9, 2020, national governmental authorities imposed strict control measures limiting social interactions and mobility for the whole Italian population. Leaving home was banned except for buying food or drugs or for health reasons and only community services workers (food chain and health, energy, communication, or security services) were allowed to circulate. All routine outpatient healthcare activities were canceled or postponed by local health authorities to contain the number of outpatients accessing healthcare facilities, hoping to reduce the spreading of infection. In particular, the Local Health Trust of Bologna (LHTB) recommended all health facilities cancel non-urgent scheduled visits, tests, and admissions, and reduce the availability of high-priority visits and tests.

We hypothesize that strict lockdown measures and healthcare organizational changes due to the COVID-19 epidemic may have worsened major clinical outcomes among patients with PD, AP, or VP. Thus, we designed a study with the following aims: (1) to describe healthcare services change in the first epidemic bout, including the lockdown period and the next period with lower epidemic risk, in cohorts of people with PD, AP, or VP [ParkLink Bologna cohort (7)] and a matched general population control cohort; (2) to compare the occurrence of PD-related major clinical outcomes of the first 7 months of the epidemic in 2020 with the same period of 2019, in the same cohorts; (3) to analyze the demographic and clinical factors associated with PD-related major clinical outcomes and death in the PD cohort.

The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) (8) and the RECORD (The REporting of studies Conducted using Observational Routinely-collected health Data) (9) guidelines were followed.

On March 1, 2020, the ParkLink Bologna record linkage system counted 1,255 participants. After excluding those dead before the start of the study (218) and those pending diagnostic definition (86), the ParkLink cohort included 759 subjects with PD (mean age 75.3 years), 93 with AP (78.5 years), and 99 with VP (83.2 years). The control cohort included 9,226 subjects (76.3 years). Demographic and clinical characteristics are summarized in Table 2. People with AP and VP were older and had more comorbidities (congestive heart failure, cerebrovascular disease, dementia, chronic pulmonary disease, diabetes, and renal disease). Compared to PD, they had a higher mean age at onset, different clinical features, and different drug treatment patterns.

During the first 7 months of the COVID-19 epidemic bout, including 3 months of strict social lockdown measures and radical rearrangement of healthcare organization followed by 4 months of gradual recovery, we observed a marked reduction of all scheduled healthcare services in a cohort of PD or other parkinsonism of a large province of Northern Italy. In relative terms, change in service utilization was identical to that of a control cohort matched for sex, age, residence area, and comorbidity. Compared with the 2019 pre-pandemic period, during the epidemic bout, people with PD showed a higher risk of hospitalization for PD-related major clinical outcomes, namely a three-fold risk of major injuries and infections (other than COVID-19). Moreover, in people with PD, such outcomes were independently associated with a reduction in physical therapy evaluation or treatment from 2019 to 2020. Finally, a preceding major clinical outcome was the strongest predictor of death.

During the first epidemic bout (March-May 2020), with strict lockdown measures in many countries, a meta-analysis of worldwide studies (4) found a median reduction—compared to previous periods—of 37% of any healthcare service, highest for visits (42%) and lower for hospital admissions (28%), diagnostics (31%), and therapeutics (30%). In our cohorts, we found even greater reductions for visits (57–63%), admissions (66–70%), and diagnostics (47–62%) but not for drug prescriptions. Outpatient physical therapy was the most impacted service, particularly in the PD cohort (93% of reduction). Similar data on physiotherapy in people with PD were reported in France (20). Data from 105 countries and territories covering all WHO regions report that cross-sectoral services for neurological disorders were the most frequently disrupted services (62.9%), followed by emergency/acute care (47.1%) (21). Travel restrictions due to lockdowns (81.7%) and regulatory closure of services (65.4%) were the most commonly reported causes of disruption.

Few data are available about the indirect impact of the COVID-19 epidemic on non-communicable chronic disorders. Excess mortality from cardiovascular diseases (22, 23), diseases of the respiratory system (22), cancer (24, 25), and chronic liver disease (26), possibly due to the disruption of essential health services during pandemic peaks, was observed in some European countries and the USA. Isolation measures have damaged the cognitive and mental health of people with dementia (27).

People with PD are per se at higher risk of hospital admissions due to infections (18), falls and injuries (18, 28), gastrointestinal complications (18), neuropsychiatric problems (18), and hypotension (29), and possibly thromboembolic (30) or cardiovascular events (18). In the first 7 months of the epidemic, people with PD suffered a doubling of events compared with the same period of 2019. Namely, major injuries and infections tripled, driven by a five-fold increase in limb injuries and a four-fold increase in pulmonary infections (excluding COVID-19). A possible explanation is that forced immobility due to social restriction (especially during the first 3 months of the epidemic) and the almost complete cancellation of scheduled physical therapy may have impacted motor function and the ability to walk among patients with PD. This, in turn, could have increased the risk of falls and major injuries (especially limb fractures). Pneumonia, another marker of disease progression (18), could be a direct consequence of motor impairment after a major injury [e.g., a fracture (31)] and/or due to the reduction of primary care contacts (32). Some empirical data consistently show a reduction in the daily walking activity during the confinement period compared to the pre-confinement period (33), the reduction in the amount, duration, and frequency of exercise (34, 35) and physiotherapy (20) in people with PD, with possible subjective and objective worsening of both motor and non-motor features (20, 34, 36–39).

Physical exercise is one of the milestones of PD treatment (40), improving physical functioning (41), gait (42), balance (42), quality of life (41, 43), cognition (44), and non-motor symptoms such as depression (43). Thus, our results are consistent with the hypothesis that reduction of physical activity, through restriction of both social life and physical exercise, favored negative health consequences in people living with PD (45), such as the occurrence of major clinical outcomes and possibly an increase in the risk of death.

We did not observe any impact on the AP and VP cohorts, but a statistically not significant trend of higher risk for infections and heart failure was found. This could be explained by a limited statistical power. Moreover, as people with AP have usually a more rapid disease progression than those with PD (46) and possibly are more often bedridden, mobility restrictions could have had a limited impact on the risk for injuries in this cohort.

The main strength of our study is the clinical diagnosis performed by neurologists during the day-by-day clinical activity. In a retrospective study, diagnostic assessment by a qualified neurologist is highly preferable than relying on other methods based on administrative claims data only. Our study has some limitations, too. The diagnostic criteria applied were not the most recent published criteria for PD and progressive supranuclear palsy. This fact might have led to the misdiagnosis between the categories of PD and AP, which, however, presumably occurred in few people. Moreover, the ParkLink cohort did not include the whole population of PD or parkinsonism in the area, since not all neurologists are participating in the study. However, including unselected patients with PD or parkinsonism covering both public and private sectors, as well as community and hospital-based services, we think that our sample is representative of the entire spectrum of the disease at the population level. Finally, data on some potential covariates/confounders, such as socioeconomic status and caregiver situation, were not available, and the reduction of healthcare services was defined by a non-validated measure.

The COVID-19 pandemic is an unprecedented “natural experiment” providing the opportunity to learn more about draconian national governmental decisions and healthcare system rearrangement (4) during public health emergencies. In 2020, ~1 million excess deaths occurred in high-income countries. This outcome reflects, together with mechanisms of the direct effects of the pandemic, also the indirect effects due to associated policy measures (47). Some speculated that subjects with chronic and severe neurodegenerative diseases could have been most seriously impacted by the indirect consequences of the epidemic (5). We observed a clear chronological association between mobility restrictions, regulatory closure of services (particularly regarding physiotherapy), and major clinical outcomes in a cohort of highly vulnerable patients, such as people with PD, that was not observed in a control population. Such findings may be considered by decision-makers during possible future emergencies (such as epidemics and extreme climate changes) when planning substantial health care and social rearrangements applied to large populations. Patients with chronic conditions, such as PD, should be considered vulnerable subjects and safeguarded as such, and strategies to maintain their physical activity should be implemented.

The datasets presented in this study can be found in online repositories. The names of the repository and accession number can be found at: Zenodo, https://doi.org/10.5281/zenodo.6023524.

The studies involving human participants were reviewed and approved by the Ethics Committee of the LHTB on June 25, 2015 (Reference Code: 15401). The patients/participants provided their written informed consent to participate in this study.

Emanuela Azzoni (AUSL di Bologna, Bologna, Italy), Francesca Baschieri (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Marzio Bellan (Bologna, Italy), Lidia Bettelli (AUSL di Bologna, Bologna, Italy), Giuseppe Bonavina (Montecatone Rehabilitation Institute, Imola, BO, Italy), Sabina Capellari (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Sabina Cevoli (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Piero de Carolis (Bologna, Italy), Danilo Di Diodoro (Bologna, Italy), Giovanni Fabbri (AUSL di Bologna, Bologna, Italy), Renata Ferrara (Bologna, Italy), Anna Sandra Gabellini (Bologna, Italy), Pietro Guaraldi (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Fabiola Lucchi (AUSL di Bologna, Bologna, Italy), Barbara Mostacci (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Roberta Pantieri (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Gaetano Procaccianti (Bologna, Italy), Rita Rinaldi (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Giovanni Rizzo (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy), Tommaso Sacquegna (Bologna, Italy), Giuseppe Samoggia (AUSL di Bologna, Bologna, Italy), Elisa Stivanello (AUSL di Bologna, Bologna, Italy), Antonella Tempestini (AUSL di Bologna, Bologna, Italy), and Carmelina Trocino (IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy).

LV, FB, LB, CZ, EB, RD'A, and FN conceptualized, designed the study, and contributed to the critical revision of the manuscript. LV, GC-B, PC, GG, MG, GL, SN, LS, CS, RD'A, and FN performed the execution of the study. FB, LB, and CZ prepared the study data and performed the statistical analysis. LV is the guarantor of the study, attests that all the listed authors meet authorship criteria, and no other meeting criteria have been omitted. All authors contributed to the interpretation of the results and approved the final manuscript.

This study is dedicated to the memory of Mr. Angelo Spiga, president and founder of the Associazione Parkinsoniani Pianura Est.

GC-B has received honoraria for speaking from AbbVie, Zambon, and Bial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.